Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

Safety data of REVATIO in adults were obtained from the
12-week, placebo-controlled clinical study (Study 1) and an open-label
extension study in 277 REVATIO-treated patients with PAH, WHO Group I [see Clinical
Studies].

The overall frequency of discontinuation in
REVATIO-treated patients on 20 mg three times a day was 3% and was the same for
the placebo group.

In Study 1, the adverse reactions that were reported by
at least 3% of REVATIO-treated patients (20 mg three times a day) and were more
frequent in REVATIO-treated patients than in placebo-treated patients are shown
in Table 1. Adverse reactions were generally transient and mild to moderate in
nature.

Table 1: Most Common Adverse Reactions in Patients
with PAH in Study 1 (More Frequent in REVATIO-Treated Patients than
Placebo-Treated Patients and Incidence ≥ 3% in REVATIO-Treated
Patients)

Placebo, %
(n = 70)

REVATIO 20 mg three times a day, %
(n = 69)

Placebo-Subtracted, %

Epistaxis

1

9

8

Headache

39

46

7

Dyspepsia

7

13

6

Flushing

4

10

6

Insomnia

1

7

6

Erythema

1

6

5

Dyspnea exacerbated

3

7

4

Rhinitis

0

4

4

Diarrhea

6

9

3

Myalgia

4

7

3

Pyrexia

3

6

3

Gastritis

0

3

3

Sinusitis

0

3

3

Paresthesia

0

3

3

At doses higher than the
recommended 20 mg three times a day, there was a greater incidence of some
adverse reactions including flushing, diarrhea, myalgia and visual
disturbances. Visual disturbances were identified as mild and transient, and
were predominately color-tinge to vision, but also increased sensitivity to
light or blurred vision.

The incidence of retinal
hemorrhage with REVATIO 20 mg three times a day was 1.4% versus 0% placebo and
for all REVATIO doses studied was 1.9% versus 0% placebo. The incidence of eye
hemorrhage at both 20 mg three times a day and at all doses studied was 1.4%
for REVATIO versus 1.4% for placebo. The patients experiencing these reactions
had risk factors for hemorrhage including concurrent anticoagulant therapy.

In a placebo-controlled fixed
dose titration study (Study 2) of REVATIO (starting with recommended dose of 20
mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct
to intravenous epoprostenol in patients with PAH, the adverse reactions that
were more frequent in the REVATIO + epoprostenol group than in the epoprostenol
group (greater than 6% difference) are shown in Table 2 [see Clinical
Studies].

REVATIO Injection

REVATIO injection was studied
in a 66-patient, placebo-controlled study in patients with PAH at doses
targeting plasma concentrations between 10 and 500 ng/mL (up to 8 times the
exposure of the recommended dose). Adverse events with REVATIO injection were
similar to those seen with oral tablets.

Postmarketing Experience

The following adverse reactions
have been identified during post approval use of sildenafil (marketed for both
PAH and erectile dysfunction). Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular Events

In postmarketing experience with sildenafil at doses
indicated for erectile dysfunction, serious cardiovascular, cerebrovascular,
and vascular events, including myocardial infarction, sudden cardiac death,
ventriculararrhythmia, cerebrovascular hemorrhage, transient ischemic attack,
hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral
hemorrhages have been reported in temporal association with the use of the
drug. Most, but not all, of these patients had preexisting cardiovascular risk
factors. Many of these events were reported to occur during or shortly after
sexual activity, and a few were reported to occur shortly after the use of
sildenafil without sexual activity. Others were reported to have occurred hours
to days after use concurrent with sexual activity. It is not possible to
determine whether these events are related directly to sildenafil, to sexual
activity, to the patient's underlying cardiovascular disease, or to a
combination of these or other factors.